Galactosaemia − Should It Be Screened in Newborns?

Classical galactosaemia (CG) is a disorder of galactose metabolism which results from a de!ciency of galactose-1 phosphate uridyltransferase (GALT, EC 2.7.7.12) activity caused by mutations in the GALT gene (NM_000155.3). Patients have absent or barely detectable GALT enzyme activity and present in the !rst weeks of life with life threatening illness (feeding di"culties, liver failure, sepsis, cataract) a#er the ingestion of galactose from breast milk or infant formula. A lactose-free and galactose-restricted diet is life saving and the only available treatment at this time [1]. Newborn screening for CG by measuring GALT enzyme activity [2] was introduced in the 1960s with the expectation that early diagnosis and dietary treatment would prevent severe illness in the newborn period and that patients would have a normal outcome. However, since 1982 long-term complications have been reported in the literature. At this time it is clear that, in spite of an early diagnosis and immediate start of treatment, many CG patients su$er from long-term complications a$ecting their quality of life, such as impaired cognitive abilities, language and speech defects, neurological complications, and hypergonadotropic hypogonadism in females [3-9]. %e most probable cause of these long-term complications is the persistent elevation of metabolites due to the endogenous production of galactose [10]. %e fact that long-term complications are not prevented recurrently brings up the dilemma whether galactosaemia should be screened in newborns.


INTRODUCTION
Classical galactosaemia (CG) is a disorder of galactose metabolism which results from a de ciency of galactose-1 phosphate uridyltransferase (GALT, EC 2.7.7.12) activity caused by mutations in the GALT gene (NM_000155.3). Patients have absent or barely detectable GALT enzyme activity and present in the rst weeks of life with life threatening illness (feeding di culties, liver failure, sepsis, cataract) a er the ingestion of galactose from breast milk or infant formula. A lactose-free and galactose-restricted diet is life saving and the only available treatment at this time [1].
Newborn screening for CG by measuring GALT enzyme activity [2] was introduced in the 1960s with the expectation that early diagnosis and dietary treatment would prevent severe illness in the newborn period and that patients would have a normal outcome. However, since 1982 long-term complications have been reported in the literature. At this time it is clear that, in spite of an early diagnosis and immediate start of treatment, many CG patients su er from long-term complications a ecting their quality of life, such as impaired cognitive abilities, language and speech defects, neurological complications, and hypergonadotropic hypogonadism in females [3][4][5][6][7][8][9]. e most probable cause of these long-term complications is the persistent elevation of metabolites due to the endogenous production of galactose [10]. e fact that long-term complications are not prevented recurrently brings up the dilemma whether galactosaemia should be screened in newborns.

NEWBORN SCREENING FOR CLASSICAL GALACTOSAEMIA
Newborn screening has historically been implemented with consideration of the ten principles of Wilson and Junger [11]. Some of these principles are nowadays easily dealt with in most countries: the condition should be an important health problem; facilities for diagnosis and treatment should be available; case nding should be a continuing process. However, for CG newborn screening some other principles are still subject to discussion.
There should be a suitable test or examinaƟon, which is acceptable to the populaƟon.
Classical galactosaemia is mostly screened by GALT enzyme measurement, o en combined with total galactose (TGAL) measurement. Screening will result in the identi cation of false positive (FP) cases, as has been demonstrated in several reports [12,13]. It is of utmost importance to minimize the number of FP referrals, as these have been demonstrated to cause anxiety, parentchild dysfunction and alterations in parental perception of the child's health [14]. CG newborn screening in the Netherlands started in 2007 with a very high rate of FP referrals. Multiple adjustments since then in methods and cuto values have now reduced the number of false positives [13]. A study in Sweden reported a decrease in the number of FP referrals to less than 0.01%, and a positive predictive value of 64% using a two-tier test strategy of GALT enzyme measurement followed by the measurement of total galactose [15]. An important limitation of combining GALT and TGAL measurements is that children on a low lactose or lactose-free diet (i.e. parenteral feeding or hypoallergenic formula) may not demonstrate elevated TGAL values and can be missed by newborn screening.
There should be an accepted treatment for paƟents with a recognized disease. e only available treatment at this time is accepted and easily implemented: a life-long lactose-free and galactose restricted diet, which rapidly resolves the illness in the newborn period. It is advised to introduce this diet, which is in infants based on lactose free formula based on soy or a hydrolysate, as soon as the diagnosis is suspected, without awaiting results of diagnostic tests [16].
The natural history should be adequately understood and there should be a recognizable latent or early symptomaƟc state.
Depending on the day of screening, most patients will be symptomatic and may already be hospitalized at the time of diagnosis by newborn screening [13]. However, early diagnosis and an immediate start of treatment signi cantly reduce morbidity and mortality. In Germany Schweitzer-Krantz (2003) demonstrated that early detection with newborn screening performed at day 5 prevented mortality in the rst weeks of life, with death reported in 19/49 patients diagnosed before the implementation of newborn screening and 1/99 diagnosed a er the start of newborn screening [17]. In Sweden only 4 CG patients diagnosed before the start of screening in 1967 survived, while since then only one patient has died [15]. Unfortunately, early diagnosis and treatment do not prevent long-term complications [17,18].
There should be a policy on whom to treat as paƟents.
Newborn screening o en results in the detection of individuals with previously unreported phenotypes and genotypes, for whom the need for treatment and the potential outcomes are unclear. Indeed, in the Netherlands, a er the start of CG newborn screening, 14% of the diagnosed patients had a previously unreported phenotype and genotype. ese individuals did not demonstrate any symptoms at the time of diagnosis while still being exposed to galactose, and some demonstrated normal metabolite levels a er the start of dietary treatment. e recent international guideline for CG recommends dietary treatment in all patients with GALT enzyme activity <10%, and states that there is insu cient evidence whether patients with 10-15% of GALT enzyme activity need to be treated. In the Netherlands, currently all the patients with enzyme activity below 15% are treated. Future studies on the need for treatment and the outcome of these patients are warranted [13,16].
The cost of case finding should be economically balanced in relaƟon to possible expenditure on medical care as a whole.
A small number of studies evaluating cost bene ts with di erent methods provide contradictory results [19][20][21].

DISCUSSION AND CONCLUSION
Currently newborn screening is performed in 9 European countries: Austria, Estonia (on a research basis), Germany, Greece, Italy, the Netherlands, Spain, Switzerland and Ireland. Two recent papers discussed the appropriateness of galactosaemia newborn screening. Varela Lema et al. (2016) concluded from their systematic review that there was insu cient evidence to establish the appropriateness of CG newborn screening, but that health benefIts could be expected if early diagnosis and treatment is achieved [22]. A Cochrane review published in 2017 concluded that it is not possible to draw conclusions based on randomized controlled studies, but that there are uncontrolled studies which support the e cacy of newborn screening for CG and that a number of reviews and economic analyses of non-trial literature suggest that screening is appropriate [23].
e striking e ects of early diagnosis on the morbidity and mortality of patients in the rst weeks of life strongly con rm the appropriateness of CG newborn screening, even when taking into consideration the fact that early diagnosis does not prevent long-term complications and the lack of insight into the cost-bene t ratios. However, with the implementation of CG newborn screening, It is of utmost importance to minimize the number of FP referrals and to educate the professionals involved in the treatment that if TGAL is one of the screening parameters newborns on low lactose diets may not be detected by the screening.
typical clinical picture of galactosaemia. ere were two asymptomatic patients, however, in whom only trace amounts of galactose were detected in blood and urine. All these patients were treated with a galactose-free diet.
During the period of 1976-1978 NBS for galactosaemia was replaced by selective screening, so now newborns with a family risk are investigated (on their rst day of life) and also infants with clinical signs and symptoms. At the same time quantitative enzyme assay was performed in order to identify carriers of galactosaemia among those families in which the newborns presented with decreased or zero activity of GALT. Such management enabled the detection of new families at risk. en, until 1984, while continuing selective screening, NBS for galactosaemia was reimplemented using both methods: the Beutler and Baluda and the Guthrie tests. e latter one could identify patients with a lack of either GALT or galactokinase activity. Among the over 155 thousand newborns investigated by both methods, one case of classical galactosaemia was detected -but at the time of diagnosis this child was already symptomatic [2].
Based on such observation as the fact that signi cantly more patients were diagnosed through selective screening (i.e. by clinical symptoms) than through NBS and the failure to prevent the occurrence of clinical signs and symptoms (including deaths) in those cases which had been detected by NBS, the decision to cease NBS for galactosaemia was undertaken (6).
It was only in the 1990s that controversies regarding NBS for galactosaemia appeared in the literature [7]. Currently it is still a subject of debate.